For over one hundred years, organic nitrates such as nitroglycerin and amyl nitrite, among others, have been used to relieve anginal pain and treat heart disease (Reeves. J. T., 1995, NIPS. 10, 141). The beneficial use of these compounds is due to their ability; once administered to subject, to induce dilation of the vascular system (i.e., arteries and veins) resulting in decrease in blood pressure and attenuation of the pre-load on the heart.
Nitroglycerin or glycerol trinitrate is an organic nitrate ester which, when administered to a subject, is converted biologically to nitric oxide ("NO"), a pharmacologically active metabolite. NO, for example, activates soluble guanylate cyclase in vascular smooth muscle cells which in turn increases cyclic guanosine monophosphate (cGMP) resulting in vasorelaxation and ultimately leading to vasodilation and a reduction in blood pressure. However, the effectiveness of nitroglycerin and other organic nitrates having vasodilating activity is greatly diminished because the recipient of the organic nitrate rapidly develops a tolerance to the beneficial effects of the organic nitrate.
Tolerance to the vascular and anti-anginal effects of nitroglycerin and other organic nitrates can develop at low dosages as well as at high dosages. As a result, the organic nitrate loses its effectiveness during sustained therapy and increasing amounts of the organic nitrate must be administered to achieve the same effect. As nitrate tolerance progresses, the effectiveness of nitroglycerin and other organic nitrates are further limited and increased dosages have little or no effect on vasorelaxation or vasodilation (see, e.g., Bogaert, M., 1991, J. Cardiovas. Pharmacol. 17 (Suppl. 3), S313; and Unger, P., et al., 1991, J. Cardiovasc. Pharmacol. 17 (Suppl. 3), S300). Furthermore, in certain circumstances, the administration of an organic nitrate to a patient who is nitrate tolerant may result in vasoconstriction, and not vasodilation (Caramori et al., 1998, JACC 32(7), 1969; Gupte et al., 1996, Am. J. Physiol. H2447). This is potentially a dangerous side effect as the administration of the organic nitrate may exacerbate the very condition that it is supposed to improve. Moreover, the infusion of very high doses of organic nitrates in an attempt to overcome the development of tolerance may lead cytotoxicity and organ failure.
The precise mechanism in which tolerance of organic nitrates (e.g., nitroglycerin) develops remains unknown. Theories explaining the development of tolerance include: (1) the sulfhydryl pools necessary for the direct biotransformation of nitroglycerin into active nitric oxide are depleted by excess nitroglycerin substrate (Boesgaard, S., et al., 1991, J. Pharmacol. Exp. Ther. 258, 851); (2) the activation of vascular guanylate cyclase is diminished by nitroglycerin (Henry P. J., et al., 1989, Br. J. Pharmacol. 98, 757); or (3) the rate of cGMP degradation may be increased due to enhanced of cGMP phosphodiesterase during tolerance to nitroglycerin (Axelsson, K. L., et al., 1987, Drugs 33, 63). Additionally, neurohormonal activation and increase in plasma volume have recently been incriminated in tolerance development.
Attempts to avoid or reduce the development of nitrate tolerance have included the use of antioxidants such as vitamins E and C. (Munzel et al., 1998, Am. J. Cardiol. 81 (1A), 30A). Other methods include the administration of reduced glutathione or cysteine and the pretreatment with angiotensin II converting enzyme inhibitors or angistensin II receptor antagonist. Likewise, some success has been achieved with thromboxane receptor antagonists to inhibit vasoconstriction associated with organic nitrate administration (Gupte et al., 1996, Am. J. Physiol. H2447). However, these methods have produced conflicting results.
In view of the above, and because nitrates are considered as first-line therapy, there is a need in the art for methods of potentiating (i.e., increasing the effectiveness of) organic nitrates being administered to subject who does not exhibit a tolerance for organic nitrates. Likewise, there is a need in the art for methods of increasing the effectiveness of organic nitrates being administered to a subject who already exhibits a tolerance to organic nitrates.
Accordingly, it is an object of the present invention to provide, inter alia, methods, formulations, and synergistic compositions for potentiating of organic nitrates being administered to a subject.